Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials

Lisa Jerome, Allison A Feduccia, Julie B Wang, Scott Hamilton, Berra Yazar-Klosinski, Amy Emerson, Michael C Mithoefer, Rick Doblin, Lisa Jerome, Allison A Feduccia, Julie B Wang, Scott Hamilton, Berra Yazar-Klosinski, Amy Emerson, Michael C Mithoefer, Rick Doblin

Abstract

Rationale: Posttraumatic stress disorder (PTSD) is a chronic condition that has wide-ranging negative effects on an individual's health and interpersonal relationships. Treatments with long-term benefits are needed to promote the safety and well-being of those suffering from PTSD.

Objectives: To examine long-term change in PTSD symptoms and additional benefits/harms after 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment of PTSD.

Methods: Participants received two to three active doses of MDMA (75-125 mg) during blinded or open-label psychotherapy sessions with additional non-drug therapy sessions. PTSD symptoms were assessed using the Clinician-Administered PTSD Scale for DSM IV (CAPS-IV) at baseline, 1 to 2 months after the last active MDMA session (treatment exit), and at least 12 months post final MDMA session (LTFU). A mixed-effect repeated-measures (MMRM) analysis assessed changes in CAPS-IV total severity scores. The number of participants who met PTSD diagnostic criteria was summarized at each time point. Participants completed a long-term follow-up questionnaire.

Results: There was a significant reduction in CAPS-IV total severity scores from baseline to treatment exit (LS mean (SE) = - 44.8 (2.82), p < .0001), with a Cohen's d effect size of 1.58 (95% CI = 1.24, 1.91). CAPS-IV scores continued to decrease from treatment exit to LTFU (LS mean (SE) = - 5.2 (2.29), p < .05), with a Cohen's d effect size of 0.23 (95% CI = 0.04, 0.43). The number of participants who no longer met PTSD criteria increased from treatment exit (56.0%) to LTFU (67.0%). The majority of participants reported benefits, including improved relationships and well-being, and a minority reported harms from study participation.

Conclusions: PTSD symptoms were reduced 1 to 2 months after MDMA-assisted psychotherapy, and symptom improvement continued at least 12 months post-treatment. Phase 3 trials are investigating this novel treatment approach in a larger sample of participants with chronic PTSD.

Trial registration: clinicaltrials.gov Identifier: NCT00090064, NCT00353938, NCT01958593, NCT01211405, NCT01689740, NCT01793610.

Keywords: Long-term follow-up; MDMA; MDMA-assisted psychotherapy; PTSD.

Conflict of interest statement

Lisa Jerome, Allison Feduccia, and Julie Wang received salary support for full-time employment with MPBC. Scott Hamilton, Mt Tam Data Analysis, received salary support from MPBC as an independent biostatistician. Berra Yazar-Klosinski received salary support for full-time employment with MAPS. Amy Emerson received salary support for full-time employment with MPBC. Michael Mithoefer received salary support from MPBC as a clinical investigator and clinical trial medical monitor as well as for training and supervision of research psychotherapists. Rick Doblin received salary support for full-time employment with MAPS.

Figures

Fig. 1
Fig. 1
Study consort flow diagram

References

    1. Ardito RB, Rabellino D. Therapeutic alliance and outcome of psychotherapy: historical excursus, measurements, and prospects for research. Front Psychol. 2011;2:270.
    1. Baggott MJ, Kirkpatrick MG, Bedi G, de Wit H. Intimate insight: MDMA changes how people talk about significant others. J Psychopharmacol. 2015;29:669–677.
    1. Baggott MJ, Coyle JR, Siegrist JD, Garrison KJ, Galloway GP, Mendelson JE. Effects of 3,4-methylenedioxymethamphetamine on socioemotional feelings, authenticity, and autobiographical disclosure in healthy volunteers in a controlled setting. J Psychopharmacol. 2016;30:378–387.
    1. Barone W, Beck J, Mitsunaga-Whitten M, Perl P. Perceived benefits of MDMA-assisted psychotherapy beyond symptom reduction: qualitative follow-up study of a clinical trial for individuals with treatment-resistant PTSD. J Psychoactive Drugs. 2019;51:199–208.
    1. Batelaan NM, Bosman RC, Muntingh A, Scholten WD, Huijbregts KM, van Balkom A. Risk of relapse after antidepressant discontinuation in anxiety disorders, obsessive-compulsive disorder, and post-traumatic stress disorder: systematic review and meta-analysis of relapse prevention trials. BMJ (Clinical research ed) 2017;358:j3927.
    1. Bedi G, Phan KL, Angstadt M, de Wit H. Effects of MDMA on sociability and neural response to social threat and social reward. Psychopharmacology. 2009;207:73–83.
    1. Bedi G, Hyman D, de Wit H. Is ecstasy an “empathogen”? Effects of +/−3,4-methylenedioxymethamphetamine on prosocial feelings and identification of emotional states in others. Biol Psychiatry. 2010;68:1134–1140.
    1. Bedi G, Cecchi GA, Slezak DF, Carrillo F, Sigman M, de Wit H. A window into the intoxicated mind? Speech as an index of psychoactive drug effects. Neuropsychopharmacology. 2014;39:2340–2348.
    1. Bershad AK, Miller MA, Baggott MJ, de Wit H. The effects of MDMA on socio-emotional processing: does MDMA differ from other stimulants? J Psychopharmacol. 2016;30:1248–1258.
    1. Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Gusman FD, Charney DS, Keane TM. The development of a clinician-administered PTSD scale. J Trauma Stress. 1995;8:75–90.
    1. Carhart-Harris RL, Wall MB, Erritzoe D, Kaelen M, Ferguson B, De Meer I, Tanner M, Bloomfield M, Williams TM, Bolstridge M, Stewart L, Morgan CJ, Newbould RD, Feilding A, Curran HV, Nutt DJ. The effect of acutely administered MDMA on subjective and BOLD-fMRI responses to favourite and worst autobiographical memories. Int J Neuropsychopharmacol. 2014;17:527–540.
    1. Carhart-Harris RL, Murphy K, Leech R, Erritzoe D, Wall MB, Ferguson B, Williams LT, Roseman L, Brugger S, De Meer I, Tanner M, Tyacke R, Wolff K, Sethi A, Bloomfield MA, Williams TM, Bolstridge M, Stewart L, Morgan C, Newbould RD, Feilding A, Curran HV, Nutt DJ. The effects of acutely administered 3,4-methylenedioxymethamphetamine on spontaneous brain function in healthy volunteers measured with arterial spin labeling and blood oxygen level-dependent resting state functional connectivity. Biol Psychiatry. 2015;78:554–562.
    1. Cipriani A, Williams T, Nikolakopoulou A, Salanti G, Chaimani A, Ipser J, Cowen PJ, Geddes JR, Stein DJ. Comparative efficacy and acceptability of pharmacological treatments for post-traumatic stress disorder in adults: a network meta-analysis. Psychol Med. 2018;48:1975–1984.
    1. Dolder PC, Muller F, Schmid Y, Borgwardt SJ, Liechti ME. Direct comparison of the acute subjective, emotional, autonomic, and endocrine effects of MDMA, methylphenidate, and modafinil in healthy subjects. Psychopharmacology. 2018;235:467–479.
    1. Dorrepaal E, Thomaes K, Smit JH, van Balkom AJ, van Dyck R, Veltman DJ, Draijer N. Stabilizing group treatment for complex posttraumatic stress disorder related to childhood abuse based on psycho-education and cognitive behavioral therapy: a pilot study. Child Abuse Negl. 2010;34:284–288.
    1. Edmond T, Rubin A. Assessing the long-term effects of EMDR: results from an 18-month follow-up study with adult female survivors of CSA. J Child Sex Abus. 2004;13:69–86.
    1. Eftekhari A, Ruzek JI, Crowley JJ, Rosen CS, Greenbaum MA, Karlin BE. Effectiveness of national implementation of prolonged exposure therapy in Veterans Affairs care. JAMA Psychiatry. 2013;70:949–955.
    1. Feduccia AA, Mithoefer MC. MDMA-assisted psychotherapy for PTSD: are memory reconsolidation and fear extinction underlying mechanisms? Prog Neuro-Psychopharmacol Biol Psychiatry. 2018;84:221–228.
    1. Feduccia AA, Holland J, Mithoefer MC. Progress and promise for the MDMA drug development program. Psychopharmacology. 2018;235:561–571.
    1. Feduccia AA, Jerome L, Yazar-Klosinski B, Emerson A, Mithoefer M, Doblin R. Breakthrough for trauma treatment: safety and efficacy of MDMA-assisted psychotherapy compared to paroxetine and sertraline. Front Psychiatry. 2019;10:1–7.
    1. Gamma A, Buck A, Berthold T, Liechti ME, Vollenweider FX. 3,4-Methylenedioxymethamphetamine (MDMA) modulates cortical and limbic brain activity as measured by [H215O]-PET in healthy humans. Neuropsychopharmacology. 2000;23:388–395.
    1. Gasser P, Holstein D, Michel Y, Doblin R, Yazar-Klosinski B, Passie T, Brenneisen R. Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. J Nerv Ment Dis. 2014;202:513–520.
    1. Goetter EM, Bui E, Ojserkis RA, Zakarian RJ, Brendel RW, Simon NM. A systematic review of dropout from psychotherapy for posttraumatic stress disorder among Iraq and Afghanistan combat veterans. J Trauma Stress. 2015;28:401–409.
    1. Gorman I, Belser AB, Jerome L, Hennigan C, Shechet B, Hamilton S, Yazar-Klosinski B, Emerson A, Feduccia AA. Posttraumatic growth after MDMA-assisted psychotherapy for posttraumatic stress disorder. J Trauma Stress. 2020;33:161–170.
    1. Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol. 2016;30:1181–1197.
    1. Grob CS, Danforth AL, Chopra GS, Hagerty M, McKay CR, Halberstadt AL, Greer GR. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry. 2011;68:71–78.
    1. Grof S. LSD psychotherapy: 4th edition. Santa Cruz: Multidisciplinary Association for Psychedelic Studies; 2008.
    1. Hogberg G, Pagani M, Sundin O, Soares J, Aberg-Wistedt A, Tarnell B, Hallstrom T. Treatment of post-traumatic stress disorder with eye movement desensitization and reprocessing: outcome is stable in 35-month follow-up. Psychiatry Res. 2008;159:101–108.
    1. Hoge CW, Castro CA, Messer SC, McGurk D, Cotting DI, Koffman RL. Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care. N Engl J Med. 2004;351:13–22.
    1. Imel ZE, Laska K, Jakupcak M, Simpson TL. Meta-analysis of dropout in treatments for posttraumatic stress disorder. J Consult Clin Psychol. 2013;81:394–404.
    1. Javidi H, Yadollahie M. Post-traumatic stress disorder. Int J Occup Environ Med. 2012;3:2–9.
    1. Johnson DR, Rosenheck R, Fontana A, Lubin H, Charney D, Southwick S. Outcome of intensive inpatient treatment for combat-related posttraumatic stress disorder. Am J Psychiatry. 1996;153:771–777.
    1. Kadel R, Kip K (2012) A SAS macro to compute effect size (Cohen’s d) and its confidence interval from raw survey data. Proceedings of the annual southeast SAS users group conference
    1. Kamilar-Britt P, Bedi G. The prosocial effects of 3,4-methylenedioxymethamphetamine (MDMA): controlled studies in humans and laboratory animals. Neurosci Biobehav Rev. 2015;57:433–446.
    1. Kessler RC, Ames M, Hymel PA, Loeppke R, McKenas DK, Richling DE, Stang PE, Ustun TB. Using the World Health Organization health and work performance questionnaire (HPQ) to evaluate the indirect workplace costs of illness. J Occup Environ Med. 2004;46:S23–S37.
    1. Kirkpatrick MG, Baggott MJ, Mendelson JE, Galloway GP, Liechti ME, Hysek CM, de Wit H. MDMA effects consistent across laboratories. Psychopharmacology. 2014;231:3899–3905.
    1. Kline AC, Cooper AA, Rytwinksi NK, Feeny NC. Long-term efficacy of psychotherapy for posttraumatic stress disorder: a meta-analysis of randomized controlled trials. Clin Psychol Rev. 2018;59:30–40.
    1. Koenen KC, Ratanatharathorn A, Ng L, McLaughlin KA, Bromet EJ, Stein DJ, Karam EG, Meron Ruscio A, Benjet C, Scott K, Atwoli L, Petukhova M, Lim CCW, Aguilar-Gaxiola S, Al-Hamzawi A, Alonso J, Bunting B, Ciutan M, de Girolamo G, Degenhardt L, Gureje O, Haro JM, Huang Y, Kawakami N, Lee S, Navarro-Mateu F, Pennell BE, Piazza M, Sampson N, Ten Have M, Torres Y, Viana MC, Williams D, Xavier M, Kessler RC. Posttraumatic stress disorder in the World Mental Health Surveys. Psychol Med. 2017;47:2260–2274.
    1. Lee DJ, Schnitzlein CW, Wolf JP, Vythilingam M, Rasmusson AM, Hoge CW. Psychotherapy versus pharmacotherapy for posttraumatic stress disorder: systemic review and meta-analyses to determine first-line treatments. Depress Anxiety. 2016;33:792–806.
    1. Merz J, Schwarzer G, Gerger H (2019) Comparative efficacy and acceptability of pharmacological, psychotherapeutic, and combination treatments in adults with posttraumatic stress disorder: a network meta-analysis. JAMA Psychiatry
    1. Mithoefer M (2017) A manual for MDMA-assisted psychotherapy in the treatment of posttraumatic stress disorder; Version 8.1,
    1. Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Doblin R. The safety and efficacy of ± 3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. J Psychopharmacol. 2011;25:439–452.
    1. Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Martin SF, Yazar-Klosinski B, Michel Y, Brewerton TD, Doblin R. Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. J Psychopharmacol. 2013;27:28–39.
    1. Mithoefer MC, Grob CS, Brewerton TD. Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA. Lancet Psychiatry. 2016;3:481–488.
    1. Mithoefer MC, Mithoefer AT, Feduccia AA, Jerome L, Wagner M, Wymer J, Holland J, Hamilton S, Yazar-Klosinski B, Emerson A, Doblin R. 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. Lancet Psychiatry. 2018;5:486–497.
    1. Mithoefer MC, Feduccia AA, Jerome L, Mithoefer A, Wagner M, Walsh Z, Hamilton S, Yazar-Klosinski B, Emerson A, Doblin R. MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials. Psychopharmacology. 2019;236:2735–2745.
    1. Mott JM, Mondragon S, Hundt NE, Beason-Smith M, Grady RH, Teng EJ. Characteristics of U.S. veterans who begin and complete prolonged exposure and cognitive processing therapy for PTSD. J Trauma Stress. 2014;27:265–273.
    1. Nagy LM, Morgan CA, 3rd, Southwick SM, Charney DS. Open prospective trial of fluoxetine for posttraumatic stress disorder. J Clin Psychopharmacol. 1993;13:107–113.
    1. Oehen P, Traber R, Widmer V, Schnyder U. A randomized, controlled pilot study of MDMA (± 3,4-methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic post-traumatic stress disorder (PTSD) J Psychopharmacol. 2013;27:40–52.
    1. Ot’alora GM, Grigsby J, Poulter B, Van Derveer JW 3rd, Giron SG, Jerome L, Feduccia AA, Hamilton S, Yazar-Klosinski B, Emerson A, Mithoefer MC, Doblin R (2018) 3,4-Methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress disorder: a randomized phase 2 controlled trial. J Psychopharmacol 32:1295–1307
    1. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007;164:1035–1043.
    1. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266–1277.
    1. Resick PA, Nishith P, Weaver TL, Astin MC, Feuer CA. A comparison of cognitive-processing therapy with prolonged exposure and a waiting condition for the treatment of chronic posttraumatic stress disorder in female rape victims. J Consult Clin Psychol. 2002;70:867–879.
    1. Schmid Y, Hysek CM, Simmler LD, Crockett MJ, Quednow BB, Liechti ME. Differential effects of MDMA and methylphenidate on social cognition. J Psychopharmacol. 2014;28:847–856.
    1. Schnurr PP. The rocks and hard places in psychotherapy outcome research. J Trauma Stress. 2007;20:779–792.
    1. Solomon Z, Shklar R, Mikulincer M. Frontline treatment of combat stress reaction: a 20-year longitudinal evaluation study. Am J Psychiatry. 2005;162:2309–2314.
    1. Steenkamp MM, Litz BT, Hoge CW, Marmar CR. Psychotherapy for military-related PTSD: a review of randomized clinical trials. JAMA. 2015;314:489–500.
    1. Swift JK, Callahan JL. Decreasing treatment dropout by addressing expectations for treatment length. Psychother Res. 2011;21:193–200.
    1. Swift JK, Greenberg RP, Tompkins KA, Parkin SR. Treatment refusal and premature termination in psychotherapy, pharmacotherapy, and their combination: a meta-analysis of head-to-head comparisons. Psychotherapy (Chic) 2017;54:47–57.
    1. Tedeschi RG, Calhoun LG. The Posttraumatic Growth Inventory: measuring the positive legacy of trauma. J Trauma Stress. 1996;9:455–471.
    1. van der Kolk BA, Spinazzola J, Blaustein ME, Hopper JW, Hopper EK, Korn DL, Simpson WB. A randomized clinical trial of eye movement desensitization and reprocessing (EMDR), fluoxetine, and pill placebo in the treatment of posttraumatic stress disorder: treatment effects and long-term maintenance. J Clin psychiatry. 2007;68:37–46.
    1. Wagner MT, Mithoefer MC, Mithoefer AT, MacAulay RK, Jerome L, Yazar-Klosinski B, Doblin R. Therapeutic effect of increased openness: investigating mechanism of action in MDMA-assisted psychotherapy. J Psychopharmacol. 2017;31:967–974.
    1. Young MB, Andero R, Ressler KJ, Howell LL. 3,4-Methylenedioxymethamphetamine facilitates fear extinction learning. Transl Psychiatry. 2015;5:e634.
    1. Young MB, Norrholm SD, Khoury LM, Jovanovic T, Rauch SAM, Reiff CM, Dunlop BW, Rothbaum BO, Howell LL. Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA) Psychopharmacology. 2017;234:2883–2895.
    1. Zimmermann P, Biesold KH, Barre K, Lanczik M. Long-term course of post-traumatic stress disorder (PTSD) in German soldiers: effects of inpatient eye movement desensitization and reprocessing therapy and specific trauma characteristics in patients with non-combat-related PTSD. Mil Med. 2007;172:456–460.

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